The secretion of gonadotropin-releasing hormone (GnRH, also called LHRH) is critical for regulating the pituitary- gonadal axis and ensuring reproductive competence for virtually all vertebrates. GnRH neurons migrate from the olfactory placode across the cribriform plate and olfactory bulb, into the forebrain and hypothalamus during embryonic and early postnatal development. The pathway that GnRH neurons migrate upon consists of axons that originate in the vomeronasal organ (VNO), and project beyond the olfactory bulb directly into the rostral forebrain. There are several distinct events that determine the destination of GnRH neurons. Each of the aims in this proposal is designed to answer fundamental questions involving one or more of these events. 1. The caudal VNN makes a turn to the ventral forebrain carrying GnRH neurons with it. Aim 1 is designed to understand the role of netrins and their receptors DCC and Unc-5 in determining the ultimate destination of GnRH neurons. 2. GnRH neuron fate is determined within the olfactory placode as it develops into the VNO. Molecular cues for cell fate determination in other parts of the nervous system include Sonic hedgehog and a cast of associated signal transduction molecules. Aim 3 relates Shh signaling to GnRH neuron development. Experiments are designed to examine several animal models of altered Shh expression. 3. As GnRH neurons begin to migrate along the VNN, multiple factors likely determine the ability of GnRH neurons to migrate. Aim 2 relates GABA expression to cell motility. We will use a slice culture system in conjunction with GFP transgenic animals to analyze migration on a single cell basis. 4. GnRH neurons make their way across a unique molecular terrain that includes the extracellular matrix of the nasal septum, the cribriform plate and the forebrain. Their relationship to the environment is likely mediated through a number of cell surface glycoconjugates and extracellular matrix molecules such as laminin. Aims 1 and 4 relate cell surface and matrix molecules to migratory behavior. The overall objective is to determine the molecular basis of directed GnRH neuron migration. Kallmann syndrome and syndromes related to Shh function (Smith-Lemli-Opitz and basal cell nevus) are associated with numerous neurological problems involving the structure and function of the olfactory system and forebrain. Results from these studies will aid in our understanding of fundamental mechanisms in nervous system development.